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Imara’s Sickle Cell Disease Therapy Impresses in Phase 2 Trial
On January 6th, Boston-based biotech, Imara Inc. announced promising Phase2a trial results of its Sickle Cell Disease Drug, IMR-687. When compared to the placebo, IMR-687 was well tolerated as a monotherapy, but it reduced markers of inflammation. Additionally, the treatment arm had a lower rate of sickle cell-related pain crises.
Sickle cell disease (SCD) is a group of inherited recessive diseases that affect over 100,000 people in the US. It is characterized by hard, sticky, and sickle-shaped red blood cells (RBCs) that die earlier, leading to a constant shortage of RBCs. Additionally, they have a difficult time traveling through small blood vessels, getting stuck, and clogging the blood flow. There are only three approved FDA treatments to manage the pain crises, and one drug to improve SCD-related anemia. New treatments are necessary to manage the unmet medical needs of people living with SCD.
IMR-687 – A PDE9 Inhibitor
IMR-687 is a small molecule inhibitor of the phosphodiesterase type 9 (PDE9) enzyme, which indirectly regulates blood flow by degrading the cyclic guanosine monophosphate (cGMP) protein. IMR-687 increases cGMP levels and alleviates the disease burden for patients.
In a 93 patient Phase 2a trial, participants were treated with escalating doses of IMR-687 given once daily for 16 to 24 weeks, either as a monotherapy or in combination with hydroxyurea (HU), the standard of care. Results showed that the drug was well-tolerated as a monotherapy and in combination with HU. People treated with IMR-687 alone had less vaso-occlusive crises/sickle cell-related pain crises (VOCs/SCPCs) and hospitalizations than patients that received the placebo (VOCs/SCPCs: 58% vs 83%; hospitalizations: 33% vs 66%). Additionally, treatment with IMR-687 resulted in a reduction in markers of rupturing of red blood cells, as well as the inflammatory markers C-reactive protein (hsCRP) and amino-terminal pro-brain type natriuretic peptide (NT-proBNP).
“I am encouraged by the incremental data from this readout, especially in light of the COVID-19 pandemic challenges,” said Biree Andemariam, M.D., Associate Professor at UConn School of Medicine, Director of the New England Sickle Cell Institute at UConn Health and the lead investigator for the Phase 2a trial. “This includes a favorable safety profile of IMR-687, lower rate of VOCs/SCPCs and VOC-related hospitalizations in the Population A1 monotherapy arm, and improvements in several biomarker results across both the monotherapy and combination groups. I am also pleased by the reductions in hsCRP and NT-proBNP in the Population A1 monotherapy arm. Both are clinically utilized biomarkers of inflammation and cardiac stress, respectively, and suggest that higher doses of IMR-687 may have novel anti-inflammatory and cardiovascular benefits in sickle cell disease.”
Challenges in the Horizon
Treating the pain, anemia, and other symptoms of SCD is crucial; however, there is a push for treatments that cure the disease. Last December, CRISPR Therapeutics and Vertex Pharmaceuticals presented promising results of their Phase1/2 clinical trials for ex vivo CRISPR/Cas9 gene-edited therapy, CTX001. Results normal or near-normal levels of total and fetal hemoglobin, which are critical for oxygen transport in RBCs. Although it poses a potential risk for therapies that help control the symptoms of SCD, gene-editing technology is a new approach, with several unknowns, and it may not work in all patients.
By Daniel Ojeda, Ph.D.
Related Article: CRISPR Gene-Edited Therapy CTX001 Raises Hopes for Sickle Cell Disease and β-Thalassemia Cures
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